Two interrelated areas are being investigated: the origin of diversity of antibodies and the regulation of immune responsiveness. THE ORIGIN OF DIVERSITY OF ANTIBODIES. It is known by mRNA-DNA hybridization that the lambda gene is in less than 5 copies per haploid mouse genome. The proof of somatic diversification would be the demonstration that an inbred mouse, e.g., BALB/c, expresses significantly less than 5 lambda minus sequences somatically. At the moment 7 lambda minus sequences of BALB/c myelomas are known but this is too close to the value 5 to be significant. It is proposed to sequence normal BALB/c V lambda and count the total variants. The genetics of expression of the lambda minus chain and of responsiveness to alpha (1,3) dextran are under analysis. Mouse strains which do not normally express lambda are known and this permits a genetic study. Further, responsiveness to alpha (1,3) dextran is controlled by four loci which determine whether the response will be 1) in the lambda or kappa light chain class, 2) in the IgM or IgG class, 3) fast or slow, and 4) heterogeneous among individuals in a population. These gene loci are the heavy chain locus (allotype linked), the kappa minus locus, the kappa minus locus and the IR-1 locus (H-2 linked). The regulation of immune responsiveness. We have developed a conceptual framework in which the self-nonself discrimination is determined by a paralysis-induction decision and the class of the response is determined by a "suppression"-induction decision. A tug-of-war between inhibition and enhancement of both B minus and Tc minus cells (cooperating cells) determines whether the response will be in the cell-mediated or humoral (IgM or IgG) class. Inhibition is mediated by TI minus cells (possibly identical to TK minus cells) and induction by TC minus cells (cooperating activity). This mechanism is being analyzed by the use of a phenomenon termed abnormal induction and inhibition in which the normal association recognition of antigen is bypassed. BIBLIOGRAPHIC REFERENCES: Cytotoxic effects of antigen- and mitogen-induced T cells on various targets. Bevan, M.J. and Cohn, M. (1975). J. Immunol. 114, 559-565.